After a shakedown cruise to Honolulu, Tahiti, and American Samoa, Chicago departed Mare Island 27 July 1931 and sailed to the east coast, arriving at Fort Pond Bay, New York, 16 August. There, she became flagship of Commander, Cruisers, Scouting Force, and operated with that force until 1940.

In February 1932, Chicago, in company with other ships of the Scouting Force, conducted gunnery exercises preliminary to the annual fleet problem off the California coast. The Fleet was based on the west coast thereafter and, until 1934, operated in the Pacific, from Alaska to the Pacific Canal Zone and the Hawaiian Islands. In 1934, the annual fleet exercises were held in the Caribbean, followed in May 1934 by the Presidential Fleet Review in New York Harbor. The Scouting Force operated along the east coast and in the Caribbean until October and then returned to base at San Pedro, California. Chicago continued to operate out of San Pedro until 29 September 1940 when she sailed to Pearl Harbor.

During the next 14 months, the heavy cruiser operated out of Pearl Harbor, exercising with various task forces to develop tactics and cruising formations, and cruising to Australia and to the west coast. When the Japanese attacked Pearl Harbor, 7 December1941, Chicago was at sea with TF 12 and the Force immediately began a 5-day sweep in the Oahu-Johnston-Palmyra triangle in an effort to intercept the enemy. The Force returned to Pearl Harbor 12 December; between 14 and [27 December]], Chicago operated with TF 11 on patrol and search missions.

On 2 February1942, Chicago departed Pearl Harbor for Suva Bay where she joined the newly formed Allied naval force. During March and April, the cruiser operated off the Louisiade Archipelago, covering the attacks on Lae and Salamaua, New Guinea. In a position to intercept enemy surface units which attempted to attack Port Moresby, Chicago also provided cover for the arrival of American troops on New Caledonia.

On 1 May 1942, Chicago was ordered from Nouméa to join Commander, Southwest Pacific, and on the 4th she supported Yorktown (CV-5) in her strike against the Japanese on Tulagi, [[Solomon Islands]. On 7 May, she proceeded, with the Support Group, to intercept and attack the Japanese Port Moresby invasion group. The following day, the group underwent several Japanese air attacks, during which Chicago suffered several casualties from strafing, but drove off the planes and proceeded ahead until it was clear that the Japanese force had been turned back.

During June and July 1942, Chicago continued to operate in the Southwest Pacific. Between 7 and 9 August, she supported the initial landings on Guadalcanal and others of the Solomon Islands, beginning the US counter-offensive against Japan. On 9 August, she engaged in the Battle of Savo Island. Hit by a Japanese destroyer's torpedo, Chicago fought damage while continuing to engage until contact with the enemy was lost. Chicago was repaired at Nouméa, Sydney, and San Francisco, where she arrived 13 October.

Early in January 1943, Chicago departed San Francisco, action-bound once more. On 27 January, she sailed from Nouméa to escort a Guadalcanal convoy. On the night of the 29th, as the ships approached to that bitterly contested island, Japanese aircraft attacked the force and the Battle of Rennell Island was underway. During the attacks, two burning Japanese planes silhouetted Chicago, providing light for torpedo attacks; two hits caused severe flooding and loss of power. By the time the attack ended, fine work on board had checked Chicagos list. Louisville (CA-28)) took the disabled ship in tow and was relieved by a tug the following morning. During the afternoon, the Japanese attacked again and, despite heavy losses, managed to hit the disabled cruiser with four more torpedoes which sank her at 11d 25m S., 160d 56m E.

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